Clinical Trials Register

Summary
EudraCT Number:	2012-001288-58
Sponsor's Protocol Code Number:	40122
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-03-27
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2012-001288-58

A.3

Full title of the trial

Boosting oxytocin after trauma: The effects of intranasal oxytocin administration on emotional and motivational brain processes in PTSD

Versterken van oxytocine na trauma: De effecten van intranasale oxytocine toediening op emotionele en motivationele hersenprocessen bij PTSS

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

The effect of oxytocin in PTSD

Het effect van oxytocine bij PTSS

A.3.2

Name or abbreviated title of the trial where available

The effect of oxytocin in PTSD

Het effect van oxytocine bij PTSS

A.4.1

Sponsor's protocol code number

40122

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Academic Medical Center
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Academic Medical Center
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	ZonMw
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Academic Medical Center, Department of Psychiatry, Center for Anxiety Disorders
B.5.2	Functional name of contact point	Olff- Oxytocin research group
B.5.3	Address:
B.5.3.1	Street Address	Meibergdreef 5
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1105 AZ
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31(0)208913662
B.5.5	Fax number	+31(0)8913664
B.5.6	E-mail	m.olff@amc.uva.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Syntocinon, nasal spray 40 IU/ml
D.2.1.1.2	Name of the Marketing Authorisation holder	Defiante Farmacêutica, SA
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Nasal spray, solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intranasal use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	50-56-6
D.3.9.3	Other descriptive name	OXYTOCIN
D.3.9.4	EV Substance Code	SUB09580MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Nasal spray, solution
D.8.4	Route of administration of the placebo	Intranasal use (Noncurrent)

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Posttraumatic Stress Disorder (PTSD) according to criteria in the DSM-IV

Posttraumatische Stress Stoornis (PTSS) volgens de criteria van de DSM-IV

E.1.1.1

Medical condition in easily understood language

posttraumatic stress disorder

posttraumatische stress stoornis

E.1.1.2

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10036316
E.1.2	Term	Post-traumatic stress disorder
E.1.2	System Organ Class	10037175 - Psychiatric disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

In this functional Magnetic Resonance Imaging (fMRI) study, the primary objective is to examine the acute effects of intranasal OT administration on emotional- and reward-related brain processes in PTSD patients compared to traumatized healthy controls. Furthermore, we aim to examine gender differences in the effects of intranasal OT administration on functional (task-specific) brain activation and in structural anatomy (i.e. volume and white matter integrity) between PTSD patients and traumatized healthy controls.

Het primaire doel van deze functionele magnetische resonantie imaging (fMRI) studie is om de acute effecten van intranasale OT toediening op emotionele en motivationele hersenprocessen te onderzoeken bij PTSS patiënten, vergeleken met gezonde, getraumatiseerde controles. Verder willen we ook onderzoeken of de effecten van intransale OT toediening op functionele (taak-specifieke) hersenactivatie en of structurele anatomie (i.e. volume en witte stof intergriteit) verschillend zijn tussen mannen en vrouwen, bij PTSS patiënten, vergeleken met gezonde, getraumatiseerde controles.

E.2.2

Secondary objectives of the trial

1.We will examine possible influences of attachment style, social support, alexithymia, emotional numbing, anhedonia and history of (childhood) trauma and life events on the effects of OT administration.
2.We will investigate possible influences of (epi)genetic variations on the effect of OT administration.
3.We will investigate the potential role of endogenous steroid hormone levels (i.e. estrogen and testosterone) in the effect of OT administration.
4.Psychobiological measures such as reaction times and accuracy on the face-matching and reward tasks and heart rate, heart rate variability and skin conductance response during task execution will be collected to investigate possible effects of OT administration on these psychobiological processes.
5.OT levels will be assessed from saliva to study the effects of intranasal OT administration.

1.We zullen mogelijke invloeden hechtingsstijl, sociale steun, alexithymia, emotionele afstomping, anhedonia en geschiedenis van trauma en levensgebeurtenissen op de effecten van OT administratie onderzoeken.
2.We zullen de mogelijke invloed van (epi)genetische variatie op de effecten van OT administratie onderzoeken.
3.We zullen de potentiële rol van endogene steroïde hormoon niveau’s (i.e. oestrogeen en testosteron) op het effect van OT administratie onderzoeken
4.Psychobiologische maten zoals reactietijden en accuratesse op de emotionele gezichtentaak en de beloningstaak en hartslag, hartslag variabiliteit en skin conductance response tijdens de uitvoering van de taken zullen worden gemeten om de mogelijke effecten van OT toediening op deze psychobiologische processen te onderzoeken.
5.OT niveau’s zullen worden onderzocht in speeksel om de effecten van intranasale OT toediening te onderzoeken.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age 18 – 65 years
• Capable to read and comprehend the Dutch language
• Eligibility for MRI (i.e. no metals, pacemakers or claustrophobia)
• Exposed to a potentially traumatic event, according to PTSD A1 criterion in the DSM-IV (minimal 1 month ago), quantified as a score of 1 or higher on the Life Events Checklist (LEC).
PTSD patients:
• Current PTSD diagnosis
• CAPS score ≥ 45
Traumatized healthy controls:
• CAPS-score < 15

• Leeftijd van 18 – 65 jaar
• Voldoende beheersing van de Nederlandse taal om het te lezen en schrijven
• Geschikt voor MRI onderzoek (i.e. geen metalen, pacemakers of claustrofobie)
• Potentieel traumatische gebeurtenis meegemaakt, volgens het PTSS A1 criterium
(minimaal 1 maand geleden), gekwantificeerd als een score van 1 of hoger op de Life Events Checklist (LEC).
PTSS patienten:
• Huidige PTSS diagnose
• CAPS score ≥ 45
Getraumatiseerde, gezonde controles:
• CAPS-score < 15

E.4

Principal exclusion criteria

• Any severe or chronic systemic disease
• Current psychotic, bipolar, substance-related, severe personality disorder, or mental retardation
• Current severe depressive disorder
• Prominent current suicidal risk or homicidal ideation
• Severe cognitive impairment or a history of organic mental disorder
• History of neurological disorders (e.g., traumatic brain injury, seizure history)
• Reports of ongoing traumatization (e.g., in case of partner violence as index adult trauma)
• Evidence of clinically significant and unstable medical conditions in which OT administration is contra-indicative such as cardiovascular, gastro-intestinal, pulmonary, severe renal, endocrine or hematological disorders, glaucoma, history of epilepsy, or a stroke or myocardial infarction within the past year
• Use of certain medication: prostaglandins, certain anti-migraine medications (ergot alkaloids), ß-adrenergic receptor-blocking agents, systemic glucocorticoids and psychopharmacological medication.
• Sensitivity or allergy for OT or its components (e.g. methylhydroxybenzoate and propylhydroxybenzoate)
• Female participants: pregnancy and breast feeding (NB. Female participants with childbearing potential must have a negative pregnancy test).
Traumatized healthy controls only:
• (lifetime history of) PTSD diagnosis, major depressive disorder.
• current DSM-IV axis 1 disorder

• Een ernstige of chronische systemische ziekte
• Huidige psychotische, bipolaire, middelengerelateerde, ernstige persoonlijkheidsstoornis, of mentale retardatie
• Huidige ernstige depressieve stoornis
• Huidig suïcide risico of suïcidale ideatie
• Ernstige cognitieve beperking of een organische mentale stoornis in de anamnese
• Neurologische stoornis in de anamnese (bv. traumatisch hersenletsel, convulsies)
• Aanwijzingen voor continuerende traumatisatie (bv in het geval van partner geweld als index trauma)
• Aanwijzingen voor klinisch significante, onstabiele medische toestand, waarbij een contraindicatie bestaat voor toediening van oxytocine, zoals cardiovasculaire, gastro-intestinale, pulmonaire, renale, endocriene of hematologische stoornissen, glaucoom, epilepsie in de anamnese, of een beroerte of myocardinfarct in het afgelopen jaar.
• Het gebruik van bepaalde medicijnen: prostaglandines en bepaalde anti-migraine medicatie (ergot alkaloides), ß-adrenerge receptor-blokkers, systemische glucocorticoïden en psychofarmacologische medicatie
• Overgevoeligheid/allergie voor oxytocine of de bestanddelen (bv methylhydroxybenzoaat en propylhydroxybenzoaat)
• Vrouwelijke deelnemers: zwangerschap, borstvoeding (NB. vrouwelijk proefpersonen in de vruchtbare leeftijd moeten een negatieve zwangerschapstest hebben)
Alleen getraumatiseerde, gezonde controles:
• (geschiedenis van) PTSS diagnose of depressieve stoornis
• Een huidige DSM-IV as 1 stoornis

E.5 End points

E.5.1

Primary end point(s)

The main outcome measures of this study are the acute effects of intranasal OT administration on emotional- and reward related brain processes in men and women diagnosed with PTSD compared to traumatized healthy controls.

De primaire uitkomtsmaten van deze studie zijn de acute effecten van intranasale OT toediening op emotionele en belonigs-gerelateerde hersenprocessen bij mannen en vrouwen met PTSS, vergeleken met getraumatiseerde, gezonde controles.

E.5.1.1

Timepoint(s) of evaluation of this end point

After the second fMRI session is finished

Na voltooing van de tweede fMRI sessie

E.5.2

Secondary end point(s)

1. Answers to various questionnaires will be used to examine potential associations between the main study outcome and representations of attachment style, social support, alexithymia, emotional numbing, anhedonia and history of (childhood) trauma and life events.
2. (Epi)gentic variation will be assessed to investigate potential associations with the main study outcome.
3. Salivary levels of estradiol and testosterone will be measured during both fMRI sessions to assess the role of endogenous steroid hormone levels.
4. Reaction times and accuracy will be calculated on the face-matching and reward tasks. Heart rate, heart rate variability and skin conductance response will be measured during the fMRI protocol.
5. We will measure OT in saliva at two time points during each fMRI session to investigate the influence of intranasal OT administration on salivary OT levels.

1. Antwoorden op verschillende vragenlijsten zullen worden gebruikt om potentiële associaties tussen de primaire studie uitkomst en representaties van hechtingsstijl, sociale steun, alexithymia, emotionele afstomping, anhedonia en geschiedenis van trauma (al dan niet tijdens kindertjijd) en levensgebeurtenissen te onderzoeken.
2. (Epi)genetische variatie zal meegenomen worden om een potentiële associatie met de primaire studie uitkomstmaten te onderzoeken.
3. Niveau’s van oestrogeen en testosteron in speeksel zullen gemeten worden tijdens beide fMRI sessie om de rol van enodgene steroïde hormonale niveaus te onderzoeken.
4. Reactietijden en accuratesse zullen worden berekend voor de emotionele gezichtentaak en de beloningstaak. Hartslag, hartslag variabiliteit en skin conductance response zullen worden gemeten tijdens het fMRI protocol.
5. We zullen OT meten in speeksel op twee meetmomenten tijdens iedere fMRI sessie om de effecten van intranasale OT toediening op speeksel OT niveau’s te onderzoeken.

E.5.2.1

Timepoint(s) of evaluation of this end point

After the second fMRI session is finished

Na voltooing van de tweede fMRI sessie

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

Laatste bezoek van laatste deelnemer

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2012-03-27.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

care as usual, if necessary

care as usual, indien nodig

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-03-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-05-21

P. End of Trial
P.	End of Trial Status	Completed

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